Flosin

Uses

Flosin, a selective alpha-1 adrenergic receptor antagonist, is used for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Flosin is not used for the treatment of hypertension.

Flosin is also used to associated treatment for these conditions: Benign Prostatic Hyperplasia (BPH)

How Flosin works

The pathogenesis of benign prostatic hyperplasia is not fully understood: it is believed to involve several pathways, including inflammation, apoptosis, and cellular proliferation. Most drug therapies aim to alleviate symptoms of benign prostatic hyperplasia, silodosin included. Lower urinary tract symptoms of benign prostatic hyperplasia are categorized into three main groups: voiding or obstructive (hesitancy, slow stream, intermittency, incomplete emptying), storage or irritative (frequency, urgency, nocturia, urge urinary incontinence), and postmicturition (postvoid dribbling). Prostate contraction is the main contributor to lower urinary tract symptoms of benign prostatic hyperplasia. The smooth muscle tone of the prostate is regulated by α_1A-adrenoceptors, which are the most highly expressed subtype of α₁adrenoceptors in the human prostate tissue. It has been reported that blockade of α_1A-adrenoceptors relieves bladder outlet obstruction. Blockade of α_1D-adrenoceptors, another subtype found in prostate tissue, is believed to alleviate storage symptoms due to detrusor overactivity.

α₁-adrenoceptors are G protein-coupled receptors: upon binding of its natural ligand, norepinephrine and epinephrine, leads to the activation of phospholipase C and downstream signalling molecules, including inositol triphosphate and diacylglycerol. Ultimately, there is an increase in intracellular calcium levels and, consequently, smooth muscle contraction. Flosin is an antagonist of α₁-adrenoceptors, with the highest selectivity for the α_1A-adrenoceptor subtype. By blocking the α_1A-adrenoceptor signalling pathway, silodosin promotes prostatic and urethral smooth muscle relaxation, thereby improving lower urinary tract symptoms such as voiding. Flosin also targets afferent nerves in the bladder, relieving bladder overactivity and storage symptoms.

Dosage

Flosin dosage

The recommended dose is Flosin 8 mg orally once daily with a meal.4 mg capsules taken orally once daily with a meal for those with moderate renal impairment (CrCl 30-50 mL/min).

Side Effects

Most common adverse reactions are retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis and nasal congestion.

Toxicity

Oral LD₅₀ is 800 mg/kg in rats.

In clinical trials, postural hypotension was the most common dose-limiting adverse event. In case of drug overdose leading to hypotension, the patient should be placed in a supine position to restore blood pressure and normalize heart rate. Further measures, such as administration of intravenous fluids, may be initiated. In case of the use of vasopressors, renal function should be monitored and supported as needed. Since silodosin is highly bound to plasma proteins, dialysis is unlikely to be beneficial.

Precaution

Postural hypotension with or without symptoms (e.g. dizziness) may develop when beginning Flosin treatment. Flosin should not be used in combination with other alpha-blocker. Inform patients planning cataract surgery to notify their ophthalmologist that they are taking Flosin because of the possibility of Intraoperative Floppy Iris Syndrome (IFIS)

Interaction

Strong P-glycoprotein inhibitors (e.g., cyclosporine): Co-administration may increase plasma Flosin concentration. Concomitant use of PDE5 inhibitors with alpha-blockers including Flosin can potentially cause symptomatic hypotension.

Food Interaction

• Take with food. A moderate fat or calorie meal decreases drug exposure as well as the risk of adverse effects.

[Moderate] ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of silodosin.

The effect of a moderate-fat, moderate-calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18% to 43% and systemic exposure (AUC) by 4% to 49% across three different studies.

The maximum effect of food (i.e., coadministration with a high-fat, high-calorie meal) on the pharmacokinetics of silodosin was not evaluated.

Safety and efficacy clinical trials for silodosin were always conducted in the presence of food intake.

MANAGEMENT: Patients should be instructed to take silodosin with a meal to reduce the risk of adverse events.

Flosin Alcohol interaction

[Moderate] GENERALLY AVOID:

The concurrent use of ethanol and alpha-1 adrenergic blockers may cause increased hypotensive effects.

Patients with aldehyde dehydrogenase deficiencies (primarily Asians) may be at a higher risk of this interaction.

The mechanism has not been determined.

Data exist for prazosin and other alpha adrenergic blockers are expected to interact also.

In addition, any patients taking alpha adrenergic blockers may experience excessive orthostatic hypotension with ethanol ingestion, due to ethanol's unopposed vasodilatory effects in the presence of alpha adrenergic blockade.

Patients who develop

a flushing reaction after ethanol ingestion (indicates a possible aldehyde dehydrogenase deficiency) should be advised to avoid ethanol or limit their intake.

All patients should be warned about the possibility of orthostatic hypotension with concurrent ethanol use.

Flosin Drug Interaction

Moderate: tadalafil, metoprolol, metoprololUnknown: aspirin, aspirin, ubiquinone, rosuvastatin, duloxetine, apixaban, omega-3 polyunsaturated fatty acids, atorvastatin, pregabalin, polyethylene glycol 3350, mirabegron, acetaminophen, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, rivaroxaban

Flosin Disease Interaction

Major: hepatic impairment, severe renal impairmentModerate: hypotension, cataracts

Volume of Distribution

Flosin has an apparent volume of distribution of 49.5 L.

Elimination Route

The absolute bioavailability is approximately 32%. Following oral administration of silodosin 8 mg once daily in healthy male subjects, C_max was 61.6 ± 27.54 ng/mL and AUC was 373.4 ± 164.94 ng x hr/mL. The T_max was 2.6 ± 0.90 hours. Flosin glucuronide or KMD-3213G, the main metabolite of silodosin, has an AUC three- or four fold higher than for the parent compound.

A moderate fat or calorie meal reduces C_max by 18% to 43% and AUC by 4% to 49%, as well as T_max by about one hour. However, the US prescribing information recommends drug intake with meals to avoid the potential adverse effects associated with high plasma drug concentrations.

Half Life

The elimination half-life of silodosin is 13.3 ± 8.07 hours. KMD-3213G, the main metabolite of silodosin, has an extended half-life of approximately 24 hours.

Clearance

After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour.

Elimination Route

At 10 days following oral administration of radiolabelled silodosin, about 33.5% of the dose was recovered in urine and 54.9% was recovered in feces.

Pregnancy & Breastfeeding use

Pregnancy Category B. Flosin is not indicated for use in women. An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13-25 times the maximum recommended human exposure or MRHE of Flosin via AUC). No statistically significant teratogenicity was observed at this dose. Flosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated Flosin, which is present in human serum at approximately 4 times the level of circulating Flosin and which has similar pharmacological activity to Flosin. No effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day.

Contraindication

Patients with severe renal & hepatic impairment, concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir) and patients with a history of hypersensitivity to Flosin.

Special Warning

Pediatric patients: Flosin is not indicated for use in pediatric patients.

Geriatric use: In double-blind, placebo-controlled, 12-week clinical studies of Flosin, 259 (55.6%) were under 65 years of age, 207 (44.4%) patients were 65 years of age and over, while 60 (12.9%) patients were 75 years of age and over. Orthostatic hypotension was reported in 2.3% of Flosin patients < 65 years of age (1.2% for placebo), 2.9% of Flosin patients > 65 years of age (1.9% for placebo), and 5.0% of patients > 75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients.

Renal impairment: Flosin is contra-indicated in patients with severe renal impairment (CCr <30 mL/min). In patients with moderate renal impairment (CCr 30-50 mL/min), the dose should be reduced to Flosin 4 mg once daily taken with a meal. No dosage adjustment is needed in patients with mild renal impairment (CCr 50-80 mL/min).

Hepatic impairment: Flosin has not been studied in patients with severe hepatic impairment (Child-Pugh score > 10) and is therefore contra-indicated in these patients. No dosage adjustment is needed in patients with mild or moderate hepatic impairment.

Acute Overdose

Flosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was postural hypotension. Should overdose of Flosin lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by maintaining the patient in the supine position. If this measure is inadequate, administration of intravenous fluid should be considered. If necessary, vasopressors could be used, and renal function should be monitored and supported as needed. Dialysis is unlikely to be of significant benefit since Flosin is highly (97%) protein bound.

Storage Condition

Store in a cool and dry place, protected from light.

Innovators Monograph

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